Dr. Sylvia A. Frazier-Bowers is applying for a new K23 mentored research grant to develop a career as an independent patient-oriented clinical investigator. The research and career development plans described here will combine Dr. Frazier-Bowers' training in orthodontics and genetics and facilitate her development into a competent investigator of the human genetics of the craniofacial complex. The objectives of this proposal are to develop the candidate's expertise in conducting original and significant research of the genetic basis of congenitally missing teeth (tooth agenesis), an area of great relevance to the field of orthodontics. Despite recent advances using genetic and molecular approaches in humans and mice, little is known about the genes involved in human tooth agenesis. Determining the molecular basis for tooth agenesis is critical to the investigator's understanding of the pathogenesis of this defect, and will provide the basis for improved treatment modalities. Mutations in two genes, MSX1 and PAX9, have been identified in association with non-syndromic familial tooth agenesis. Specifically, studies in their laboratory led to the discovery that an insertion mutation in PAX9 causes molar oligodontia. They have subsequently identified two more novel mutations responsible for molar oligodontia. Based on these studies, they hypothesize that tooth agenesis arises from mutations in genes involved in tooth development, particularly MSX1 and PAX9. The long-term goals of this research are to elucidate the genetic etiology of human tooth agenesis. Aim 1 will identify, clinically characterize, and collect samples from individuals and/or families with multiple members demonstrating patterns of congenitally missing teeth. They will expand their recently established database of 134 individuals through continual screening efforts and by laterally extending the pedigrees of individuals currently identified. DNA will be harvested from blood or buccal cell samples collected from these families. Aim 2 proposes to use the collected samples to identify MSX1 and PAX9 mutations associated with molar oligodontia by sequencing these genes in 28 patients affected with molar oligodontia. These studies will help to determine if these two genes are responsible for the majority of cases of molar oligodontia, or if other key candidate genes such as LEF1, or BMP4 are responsible in some cases. Aim 3 will utilize a genome-wide screen to determine the chromosomal location of the gene causing non-syndromic mandibular incisor agenesis. Aim 4 proposes to screen candidate genes in the chromosomal region identified in Aim 3 to determine the cause of mandibular incisor agenesis. Thus, determining the genetic basis of specific patterns of tooth agenesis as proposed here has significant implications for the possible treatment of both acquired and inherited loss of teeth. This research is central to the career goals of the applicant, which are to perform independent and original research that is relevant to identifying genetic factors that lead to orthodontic problems.